Camp. Biochem. Physid. Vol. IOlA, No. 4, pp. 819-825, 1992 Printed in Great Britain
0300-9629192 $5.00+ 0.00 0 1992Pergamon Press plc
THE VASOPRESSOR ACTION OF ANGIOTENSIN SNAKE BOTHROPS JARARACA M. C.
and Z. P. PICARELLI*
ServiGo de Farmacologia, Institute Butantan, Av. Vital Brasil, [email protected]
Postal 65,05504-Sto SP, Brazil. Fax: (011) 815-1505
(Received 28 June 1991) Abstract-l.
Carotid blood pressure from anesthetized B. jururaca snakes was recorded in order to study angiotensin action in this reptile. 2. Whereas [Asn’,Val’] AI1 and AI11 were less potent than [Asp’,Ile5] AI1 and [Asp’,Val’] AII, [Sar’,Ile’] AI1 was slightly more potent. 3. Captopril abolished the responses to AI (0.01-3 pg/kg). 4. [Sar’,Ala*] AI1 was uneffective but [Sar’,Leu8] AI1 or phenoxybenzamine were able to reduce AI1 vasopressor responses. 5. These results led to the conclusion that the vasopressor response of AI1 in B. jurarucu is due to an
interaction with its own receptor but, part of the AI1 receptor population seems to be coupled to the sympatho-adrenal system. Moreover, structural requirements seem to be necessary for the AI1 response in B. jururucu.
Despite the large amount of data in the literature and the amount of knowledge attained about the renin-angiotensin system in mammals, research covering this subject in nonmammalian species was only initiated two decades ago. Hence, useful information concerning the components of the reninangiotensin system from elasmobranchs to mammals have been acquired (Capelli et al., 1970; Taylor, 1977; Nishimura, 1980; Wilson, 1984). The vasopressor action of exogenous angiotensin was observed in various vertebrate species, even when endogenous renin-like activity was not demonstrated, thus indicating the phylogenetic preservation of the angiotensin receptor (Nishimura et al., 1970; Opdyke and Holcombe, 1976). As it occurs in mammals, angiotensin II (AII) seems to produce its effect in nonmammalian species by interacting with its own receptor and also by releasing catecholamines. The contribution of this last action to the final vasopressor response of AI1 seems to be prominent in nonmammalian vertebrates. Studies using the Brazilian poisonous snake Bothraps juraraca (BJ) were able to demonstrate the presence of a powerful converting enzyme activity (peptidil-dipeptidase EC 126.96.36.199) in its plasma (Lavras et al., 1978, 1980). Furthermore, kidney extract from this snake produced a vasopressor effect in the rat, suggesting a renin-like activity in that organ and the presence of angiotensinogen in the snake plasma (Gervitz et al., 1987). Therefore, it was judged interesting to study the mechanism of action of angiotensin on the carotid blood pressure of the snake Bothrops juraraca, and also to try to characterize the receptor responsible for that action. This paper will present the results *To whom correspondence should be addressed.
of such a study. The relationship between the reninangiotensin system @AS) and the control of blood pressure (BP) in B. jururuca will also be discussed. MATERIALS
Adult male or female Bothrops jururacu snakes, weighing IO&200 g, collected from the wild and classified by the Se&i0 de Herpetologiu, Institute Butuntun, were used. They were maintained for at least 15 days before being used in wooden cages, under standard conditions, as described by Breno er al. (1990). Drugs
The following drugs were used: sodium pentobarbital, a gift from Abbott Laboratories, Brazil; sodium heparin (Liquemine, Roche Laboratories, Brazil); [Asn’,Vals] AI1 (Hypertensin, Ciba Laboratories, Switzerland); [Asp’,Ile5] AI, [Asp’,IleS] AII, [Sar’,Ile’] AII, [Iles] AIII, [Sar’,Leus] AI1 and [Sar’,Ala*] AI1 triacetate, synthetized at the Departament of Biophysics, Escola Paulista de Medicina, Brazil; [Asp’,Va15]AI1 and noradrenaline bitartrate (Sigma Chemical Company, U.S.A.); Captopril (Cuporen) kindly supplied by Squibb Laboratories, Brazil; phenoxybenzamine hydrochloride (Smith, Kline and French Laboratories, U.S.A.). All drugs were dissolved in 0.6% NaCl, except phenoxybenzamine hydrochloride that was dissolved in 95% ethanol and then diluted with 0.6% NaCl. Blood pressure recording
Snakes were anesthetized with sodium pentobarbital (30 mg/kg) administered under the skin of the anterior third of the snake body dorsal part. Blood pressure was recorded from the cannulated carotid artery, on a smoked drum, with the aid of a mercury manometer (Condon, 195I). Administration of drugs, including the anticoagulant heparin (4OOLU./kg), was made through a polyethylene catheter (PE-20), previously filled with 0.6% NaCl, inserted into the right renal vein. The volume of the drugs, injected as bolus, never exceeded 0.3 ml and was always flushed in with 0.2 ml of 0.6% NaCl.
M. C. BRENOand 2. P. PlCARELLl
produced by the low or the high dose was 10-18 or 35-50 min, respectively. No tachyphylaxis was noticed with any of the angiotensin analogues tested. As illustrated in Fig. 1, whereas the decapeptide [Asp’,Ile’] AI and the octapeptide [Asp’,Ile5] AI1 were equipotent in their vasopressor effects, [Iles] AI11 was the least potent agonist assayed. Their mean ED are indicated in Table 1. This Table also shows that a valine residue at position 5 of the molecule did not alter the potency of angiotensin II. However, the concomitant presence of asparagine and valine residues at position 1 and 5, respectively, made the molecule less active, its ED being lo-fold greater than that of [Asp’,Ile5] AI1 or [Asp’,Val’] AII. [Sar’Jle’] AI1 was the most potent among the angiotensin analogues tested in the blood pressure of Bothrops jururucu, as indicated in Table 1. Its ED% was almost half of that of [Asp’,IleS] AII.
Dose-response curves for angiotensin analogues or noradrenaline were made by the method of simple doses. For each agonist only one dose-response curve per animal was made. The mean and SEM of the agonist doses producing 50% of its maximum effect (ED& in all the curves was calculated. When angiotensin antagonists [Sar’,Leus] AI1 and [Sar’,Ala’] AI1 or the a-adrenoceptor blocker (phenoxybenzamine-PBZ) were used, they were allowed to act for 20 to 30 or 60 min, respectively; sufficient time to establish, before any agonist administration, an effective antagonism. Captopril was given 20min before starting any agonist curve. Statistical analysis The results expressed as means f standard error of the mean, were compared by the unpaired Student’s t-test. RESULTS
Converting enzyme inhibition
The mean blood pressure of anesthetized Bothrops juraruca prior to administration of any drug was found to be 28.89 f 10.87 mmHg (N = 37). All the angiotensin analogues tested caused a dosedependent hypertensive effect (Fig. 1). A short latency period was observed with [Asp’,IleS] AI and [Ile5] AI11 but no appreciable latency could be noted with any of the other AI1 analogues. The duration of the hypertensive response of each of the angiotensin analogues was also dosedependent; the average duration of the response
Captopril completely abolished the vasopressor effect of AI (0.01 to 3 pg/kg). Nevertheless, doses of AI greater than the maximal one that was effective (3 pg/kg) were still able to cause a reasonable hypertensive response during the inhibitor infusion (Fig. 2). The response of [Asp’,Ile’] AI1 was not affected by this converting enzyme inhibitor; also no significant alteration in the snake basal blood pressure level was noted during its administration.
curves of angiotensin analogues on blood pressure of the snake Bothrops jararaca-animals were anesthetized with sodium pentobarbital(30 mg/kg) and heparinized (400 I.U./kg). Points and bars represent means and SEM. (e-0) [Asp’Jle’] AI; (o-_O) [Aspl,IleJ] AII; (A-A) [Ile’] AIII; n = number of snakes used. Fig. 1. Mean dose-response
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M. C. BRENOand Z. P. FWARELLI
dose [JWkg 1 Fig. 3. Mean dose-response curves of [Asp’,IleS]AI1 on Bothropsjararaca arterial blood pressure before
and after [Sar’,Leu*]AI1 (1.5 &kg/min) (A-A)
or phenoxybenxamine (PBZ-20 mg/kg
Same conditions as in Fig. 1. Points and bars represent plus 1 mg/kg/hr) CO--- 0) or both (m-m). means and SEM. *, *Significantly different (P < 0.01 or P < 0.05, Student’s r-test) from the corresponding responses obtained before any antagonist; n = number of snakes. may be obtained, being possible therefore, to compare their potencies through the analysis of their m50.
The equipotency between AI and AII, observed in this bioassay using Bothrops jararaca, suggests that the decapeptide AI has to be converted into the corresponding octapeptide analogue AI1 before producing its vasopressor effect. This was confirmed by using captopril, which completely blocked the responses of AI (0.01-3 pg/kg), without causing any alteration in the AI1 dose-response curve. These findings, besides supporting the results previously reported about the presence of converting enzyme in
Bothrops jararaca plasma (Lavras et al., 1978, 1980), demonstrate its action in vivo.
However, in the presence of captopril infusion, 10 and 30pg/kg of AI were still able to cause a significant vasopressor response. Neither a new bolus administration of the converting enzyme inhibitor, nor starting the dose-response curve by these two high doses yielded any reduction in their responses. Unlike the data obtained in other vertebrates (Nishimura, 1980; Stephens, 1981; Khosla et al., 1983; Ho et al., 1984; Harper and Stephens, 1985), these results could be indicating the presence of another converting enzyme or enzymes in Bothrops
Fig. 4. Mean dose-response curves of [Asp’Jle’] AI1 on Bothropsjararaca arterial blood pressure before l). Same conditions as in Fig. 1. Points and (O-0) and after [Sar’,Ala*] AI1 (IS &kg/min) (mbars represent means and SEM; n = number of snakes. No significant differences were observed in the responses obtained before and after the antagonist.
Angiotensin action in B. jararocu snake
Fig. 5. Mean dose-response curves of noradrenaline (NA) on Borhropsjararacu arterial blood pressure before (A-A) and after phenoxybenxamine (PBZ-2Omg/kg plus 1 mg/kg/hr) (A-A). Same conditions as in Fig. 1. Points and bars represent means and SEM. *Significantly different (P < 0.05, Student’s t-test) from the corresponding values obtained before PBZ, n = number of snakes.
jararaca blood, not affected by captopril and in such low concentration that it (they) might only be noticed during that particular condition. The possibility of a weak direct action of AI should also be considered, in view of its feeble myotropic response on isolated rat uterus and its similar sequence with AI1 backbone, essential for the angiotensin biological functions in mammals (Carlini et al., 1958; Peach, 1977). Further studies concerning this hormone receptor revealed the existence of two angiotensin receptor subtypes, one of them being directly stimulated by AI (Peach and Levens, 1980). In general, amino acid variations in positions 1, 5 and 9 have been found in mammalian and nonmammalian angiotensin molecules (Nishimura, 1980; Wilson, 1984). The angiotensin structure-activity relationship analysis, carried out in vivo and in vitro in mammalian preparations led authors to some conclusions about the relation of each amino acid present in this peptide backbone and its influence on hormone receptor binding and stimulation (Regoli et al., 1974; Khosla et al., 1974; Peach, 1977). Our experiments in Bothrops jururuca demonstrated that, as with mammals (Khosla et al., 1974; Regoli, 1974) and domestic fowl (Nishimura et al., 1982), either valine or isoleucine residue in position 5 led to equal vasopressor activity, although Va15is the natural amino acid found in all nonmammalian angiotensin molecules already described: fowl: Gullus gullus+Asp’,Va15,Ser9] AI (Nakayama et al., 1973); snake: Elaphe climocophora--[X-Asx’,Va15,Tyr9] AI (Nakayama et al., 1977), turtle: Pseudemys scripta[Asp’,Val’,His’] AI (Hasegawa et al., 1984a); bullfrog: Rana catesbeiuna+Asp’,Va15,Asn9] AI (Hasegawa et al., 1983); goosefish: Lophius litulon[Asn’,Va15,His9] AI (Hayashi et al., 1978 and
Hasegawa et al., 1984b), salmon: Oncorhynchus keta+Asp’,Va15,Asn9] AI and [Asn’,Va15,Asn9] AI (Takemoto et al., 1983), eel: Anguillu rostrutu[Asp’,Vals,Gly9] AI (Khosla et al., 1985). However, the replacement of N-terminal aspartic acid for asparagine, drastically reduced the angiotensin vasopressor potency in Bothrops jararaca, contrary to the data obtained in the majority of the mammalian bioassays but resembling data from rabbit aorta strip and fowl blood pressure where [Asn’] AI1 was also less potent than [Asp’] AI1 (Regoli et al., 1974; Nishimura et al., 1982; Nakamura et al., 1982). In addition, whereas AI11 ([des-Asp’] AII) was the least potent analogue tested, in agreement with similar mammalian data (Khosla et al., 1974; Hall et al., 1974), the amino-terminal substituted analogue [Sar’] AI1 was slightly more active than [Asp’] AII. In domestic fowl, on the other hand, either absence (AIII) or replacement of aspartic acid in position 1 of the octapeptide by asparagine or sarcosine residues, markedly decreased the vasopressor effects of these analogues (Nakamura et al., 1982; Nishimura et al., 1982). These facts were attributed to a greater resistance of [Asp’] AII, in Gallus gallus, to aminopeptidase degradation and/or a higher affinity to AI1 receptor. Nishimura et al. (1980) also reported that, in unanesthetized eels, whereas [Asn’] AI1 was a more potent vasopressor substance than [Asp’] AII, [Sar’] AI1 was less potent. Although the structure of Bothrops jararaca angiotensin is still unknown, these results point to an N-terminal requirement for the peptide vasopressor response in this snake, which is against data reported for mammals. The existence of an aminopeptidase which preferentially degrades asparagine residue and/or a change in drug-receptor affinity should be
M. C. BRENO and Z. P.
evaluated in order to clarify the reduced potency of [Asn’,Va15] AII. It is well known from mammals that AH stimulates the adrenal medulla to release adrenaline and may also interfere at different steps of the periferic noradrenergic transmission (Westfall, 1977, 1980; Story and Ziogas, 1987; Reid and Rubin, 1989). However, the mechanism by which AI1 produces its vasopressor and/or myotropic effects in nonmammalian species, particularly in reptiles is unclear, discrepancies existing in the literature. The vasopressor responses caused by [Ile’] AI1 or a homologous kidney extract in the snake Ptyus korros have been attributed to an interaction with AIIs own receptor and with an undifferentiated/unspecialized AII-a adrenergic receptor (Ho et al., 1984). This common receptor was postulated since [Sar’,Ala*] AI1 reduced both Na and AI1 responses, whereas phentolamine abolished or reduced NA or AI1 vasopressor effects, respectively. Moreover, as reserpinized snakes did not show any alteration of AI1 and NA responses, catecholamine release involvement was not considered. Ho et al. (1986), by using the hindquarter preparation of the same snake species concluded that AI1 interacted with both specific angiotensin receptors and a-andrenergic receptors. In spite of this, contractions yielded by [Ile5] AI1 on Ptyas korros isolated carotid arteries were not modified by phentolamine, suggesting no catecholamine contribution to its final response (Yung and Chiu, 1985). The presence of functionally independent angiotensin and a-adrenergic receptors was demonstrated on the dorsal aortic strips of the freshwater turtle Pseudemys scripta elegans (Stephens, 1984). Curiously, the vasopressor response of this turtle to [val’] AI1 amide (Stephens, 1984) and to [Ile’] AI1 (Zehr et nl., 1981) points to a catecholaminedependent component. Indeed, a clear agreement seems to exist when in viuo or in oitro data from turtles and snakes are compared separately but a strong discrepancy between in vitro and in vivo results from the same reptile. In Bothrops jururaca, whereas the experiments made with [Sar’,Leu’] AI1 suggest the presence of an angiotensin receptor, those made with phenoxybenzamine indicate catecholamine involvement in the AI1 response. Together, these results indicate that AI1 is producing its effect mainly by acting at its own receptor, since [Sar’,Leus] AI1 totally abolished responses to doses lower than 1 pg/kg and, markedly reduced the responses to the two higher ones. However, at least part of the AI1 receptor population Seems to be coupled to the sympatho-adrenal system, in view of the a-adrenoceptor blocker experiments. No evidence for an undifferentiated/unspecialized AI&a-adrenergic receptor was found, but the presence of independent adrenergic and angiotensin receptors was noticed in the snake. Moreover, the failure of [Sar’,Leus] AI1 to abolish the responses to the two highest doses of AI1 on Bothrops jararaca blood pressure, could be attributed to its lower effectiveness at high AI1 doses since
simultaneous infusion of [Sar’,Leu”] AI1 and phenoxybenzamine nearly suppressed these responses. [Sar’,Alas] AII, a competitive angiotensin antagonist in mammals (Pals et al., 1971), failed to modify the angiotensin dose-response curve in Bothrops jararaca differently from other nonmammalian data (Stephens, 1981; Ho et al., 1984; Harper and Stephens, 1985). Perhaps, high antagonist dosage could be more effective in that snake. AII, one of the most powerful natural vasopressor substances, has multiple biological functions in mammals as a consequence of its different sites of action. In nonmammalian species, however, the RAS has been implicated with catecholamine release and vasopressor, steroidogenic and dipsogenic actions (Carroll and Opdyke, 1982; Nishimura, 1980). In the snake Bothrops jururaca all the components of the renin-angiotensin system were demonstrated, as well as a functional angiotensin receptor in vivo. Moreover, data from R. K. Gervitz (personal communication) demonstrated the presence of renin in the snake plasma, which after incubation followed by elution of the released product from a Dowex column, increased Bothrops juraraca blood pressure, this effect being abolished by [Sar’,Leu*] AI1 treatment. These results, together with a catecholamineangiotensin relationship in Bothrops jururuca suggest, for the renin-angiotensin system of this snake, a physiological role, which may be related to blood pressure regulation, an old function of this system in many vertebrate species. REFERENCES
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